Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy

Author(s): Jiang, L; Lin, W; Zhang, C; Ash, PEA; Verma, M; Kwan, J; van Vliet, E; Yang, Z; Cruz, AL; Boudeau, S; Maziuk, BF; Lei, S; Song, J; Alvarez, VE; Hovde, S; Abisambra, JF; Kuo, M; Kanaan, N; Murray, ME; Crary, JF; Zhao, J; Cheng, J; Petrucelli, L; Li, H; Emili, A; Wolozin, B;
Year: 2021;  
Journal: Molecular Cell;  
Volume: 81;  
Issue: 20;  

The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N6-methyladenosine (m6A) modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m6A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m6A and the m6A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice. These results reveal a complex containing oTau, HNRNPA2B1, and m6A that contributes to the integrated stress response of oTau.